Skip to main content
SpringerLink
Log in

The Benefits of Early Combination Treatment of Carvedilol and an ACE-Inhibitor in Mild Heart Failure and Left Ventricular Systolic Dysfunction. The Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure Evaluation Trial (CARMEN)

  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Aims: Heart failure (HF) treatment guidelines of the ESC recommend ACE-inhibitors (ACE-I) as first-line treatment and β-blockers added if patients remain symptomatic. CARMEN explored the need for combined treatment for remodelling and order of introduction by comparing the ACE-I enalapril against carvedilol and their combination.

Methods: In a parallel-group, 3-arm study of 18 months duration, 572 mild heart failure patients were randomly assigned to carvedilol (N = 191), enalapril (N = 190) or their combination (N = 191). In the latter, carvedilol was up-titrated before enalapril. Left ventricular (LV) remodelling was assessed by transthoracic echocardiography (biplane, modified Simpson) at baseline and after 6, 12 and 18 months of maintenance therapy. Primary comparisons considered the change in LV end-systolic volume index (LVESVI) from baseline to month 18 between the combination and enalapril, and between carvedilol and enalapril.

Results: In the first primary comparison, LVESVI was reduced by 5.4 ml/m2 (p = 0.0015) in favour of combination therapy compared to enalapril. The second primary comparison tended to favour carvedilol to enalapril (NS). In the within treatment arm analyses, carvedilol significantly reduced LVESVI by 2.8 ml/m2 (p = 0.018) compared to baseline, whereas enalapril did not. LVESVI decreased by 6.3 ml/m2 (p = 0.0001) with combination therapy. All three arms showed similar safety profiles and withdrawal rates.

Conclusion: CARMEN is the first study to demonstrate that early combination of ACE-I and carvedilol reverses LV remodelling in patients with mild to moderate HF and LV systolic dysfunction. The results of the CARMEN study support a therapeutic strategy in which the institution of β-blockade should not be delayed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Remme WJ, Swedberg K. Task force for the diagnosis and treatment of chronic heart failure, European Society of Cardiology Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22:1527–1560.

    Article  CAS  PubMed  Google Scholar 

  2. Hobbs FDR, Jones MI, Allan TF, Wilson S, Tobias R. European survey of primary care physician perceptions on heart failure diagnosis and management (EURO-HF). Eur Heart J 2000;21:1877–1887.

    Article  CAS  PubMed  Google Scholar 

  3. Cleland JGF, Cohen-Solal A, Cosin Aguilar J, et al. Management of heart failure in primary care (the IMPROVEMENT of Heart Failure Programme): An international survey. Lancet 2002;360:1631–1639.

    Article  CAS  PubMed  Google Scholar 

  4. Komajda M, Follath F, Swedberg K, et al. The euro heart failure survey programme: A survey on the quality of care among patients with heart failure in Europe: Treatment. Eur Heart J 2003;24:464–474.

    Article  CAS  PubMed  Google Scholar 

  5. Greenberg B, Quinones MA, Koilpillai C, et al. Effects of long term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. Results of the SOLVD echocardiographic study. Circulation 1995;91:2573–2581.

    CAS  PubMed  Google Scholar 

  6. Doughty RN, Whalley GA, Gamble G, MacMahon S, Sharpe N. Left ventricular remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease. Australia-New Zealand heart failure research collaborative group. J Am Coll Cardiol 1997;29:1060–1066.

    Article  CAS  PubMed  Google Scholar 

  7. Senior R, Basu S, Kinsey C, Schaeffer S, Lahiri A. Carvedilol prevents remodelling in patients with left ventricular dysfunction after acute myocardial infarction. Am Heart J 1999;137:646–652.

    CAS  PubMed  Google Scholar 

  8. Yue TL, Cheng HY, Lysko PG, et al. Carvedilol, a new vasodilator and beta adrenoceptor antagonist, is an antioxidant and free radical scavenger. J Pharmacol Exp Ther 1992;263:92–98.

    CAS  PubMed  Google Scholar 

  9. Yue T, McKenna PJ, Lysko PG, Ruffolo RRJ, Feuerstein GZ. Carvedilol, a new anti-hypertensive prevents oxidation of human low density lipoprotein by macrophages and copper. Atherosclerosis 1992;97:209–216.

    CAS  PubMed  Google Scholar 

  10. Metra M, Giubbini R, Nodari S, Boldi E, Modena MG, Dei CL. Differential effects of beta-blockers in patients with heart failure: A prospective, randomized, double-blind comparison of the long-term effects of metoprolol versus carvedilol. Circulation 2000;102:546–551.

    CAS  PubMed  Google Scholar 

  11. Sanderson JE, Chan SKW, Yip G, et al. Beta-blockade in heart failure: A comparison between carvedilol with metoprolol. J Am Coll Cardiol 1999;34:1522–1528.

    Article  CAS  PubMed  Google Scholar 

  12. Packer M, Antonopoulos GV, Berlin JA, Chittams J, Konstam MA, Udelson JE. Comparative effects of carvedilol and metoprolol on left ventricular ejection fraction in heart failure: Results of a meta-analysis. Am Heart J 2001;141:899–907.

    Article  CAS  PubMed  Google Scholar 

  13. Feuerstein GZ, Yue TL. A potent antioxidant, SB209995, inhibits oxygen-radical-mediated lipid peroxidation and cytotoxicity. Pharmacology 1994;48:385–391.

    CAS  PubMed  Google Scholar 

  14. Groenning BA, Nilsson JC, Sondergaard L, et al. Antiremodelling effects on the left ventricle during beta-blockade with metoprolol in the treatment of chronic heart failure. J Am Coll Cardiol 2000;6:2072–2080.

    Article  Google Scholar 

  15. Remme WJ on behalf of the CARMEN Steering Committee and Investigators. The Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure EvaluatioN trial (CARMEN)—rationale and design. Cardiovasc Drugs Ther 2001;15:69–77.

    Article  CAS  Google Scholar 

  16. The Task Force on Heart Failure of the European Society of Cardiology. Guidelines for the diagnosis of heart failure. Eur Heart J 1995;16:741–751.

    Google Scholar 

  17. Schiller NB, Shah PM, Crawford M, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. J Am Soc Echocardiog 1989;2:358.

    CAS  PubMed  Google Scholar 

  18. Kingma JH, van Gilst WH, Peels CH, Dambrink JH, Verheugt FW, Wielenga RP. Acute intervention with captopril during thrombolysis in patients with first anterior myocardial infarction. Results from the captopril and thrombolysis study (CATS). Eur Heart J 1994;15:898–907.

    CAS  PubMed  Google Scholar 

  19. Dunnett CW. Multiple comparisons between treatments and a control. Biometrics 1961;20:482–491.

    Google Scholar 

  20. Schafer JL. Multiple imputation: A primer. Stat Methods Med Res 1999;8:3–15.

    Article  CAS  PubMed  Google Scholar 

  21. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: Executive summary. Circulation 2001;104:2996–3007.

    CAS  PubMed  Google Scholar 

  22. Cohn JN, Johnson GR, Shabetai R, et al. Ejection fraction, peak exercise oxygen consumption, cardiothoracic ratio, ventricular arrhythmias and plasma norepinephrine as determinants of prognosis in heart failure. The V-HeFT VA cooperative studies group. Circulation 1993;87:V15–V16.

    Google Scholar 

  23. White HD, Norris RM, Brown MA, et al. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 1987;76:44–51.

    CAS  PubMed  Google Scholar 

  24. Cohn JN, Ferrari R, Sharpe N on behalf of an International Forum on Cardiac Remodeling: Cardiac Remodeling: Concepts and Clinical Implications: A Consensus Paper from an International Forum on Cardiac Remodeling. J Am Coll Cardiol 2000;35:569–582.

    Article  CAS  PubMed  Google Scholar 

  25. Olsen SL, Gilbert EM, Renlund DG, Taylor DO, Yanowitz FD, Bristow MR. Carvedilol improves left ventricular function and symptoms in chronic heart failure: A double-blind randomized study. J Am Coll Cardiol 1995;25:1225–1231.

    Article  CAS  PubMed  Google Scholar 

  26. Metra M, Nardi M, Giubbini R, Dei Cas L. Effects of short-and long-term carvedilol administration on rest and exercise hemodynamic variables, exercise capacity and clinical conditions in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 1994;24:1678–1687.

    CAS  PubMed  Google Scholar 

  27. Bristow MR. Beta adrenergic receptor blockade in chronic heart failure. Circulation 2000;101:558–569.

    CAS  PubMed  Google Scholar 

  28. Poole-Wilson PA, Swedberg K, Cleland JGF, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure. Results of the Carvedilol or Metoprolol European Trial (COMET). Lancet 2003;362:7–13.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Sticares Foundation, Rhoon, The Netherlands

    Willem J. Remme

  2. University of Regensburg, Regensburg, Germany

    Guenter Riegger

  3. Frederiksberg Hospital, Frederiksberg, Denmark

    Per Hildebrandt

  4. Centre Hospitalier Pitié Salpetrière, Paris, France

    Michel Komajda

  5. St. Antonius Hospital, Nieuwegein, The Netherlands

    Wybren Jaarsma

  6. Hospital Le Molinette, Torino, Italy

    Marco Bobbio

  7. University Hospital Vall d’Hebron, Barcelona, Spain

    Jordi Soler-Soler

  8. F. Hoffmann-La Roche, Basel, Switzerland

    Armin Scherhag & Beatrix Lutiger

  9. Karolinska Hospital, Stockholm, Sweden

    Lars Rydén

Authors
  1. Willem J. Remme
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guenter Riegger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Per Hildebrandt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michel Komajda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wybren Jaarsma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marco Bobbio
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jordi Soler-Soler
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Armin Scherhag
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Beatrix Lutiger
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lars Rydén
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Remme, W.J., Riegger, G., Hildebrandt, P. et al. The Benefits of Early Combination Treatment of Carvedilol and an ACE-Inhibitor in Mild Heart Failure and Left Ventricular Systolic Dysfunction. The Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure Evaluation Trial (CARMEN). Cardiovasc Drugs Ther 18, 57–66 (2004). https://doi.org/10.1023/B:CARD.0000025756.32499.6f

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:CARD.0000025756.32499.6f

Search

Navigation